TABLE 3. Open-label investigations in patients described as refractory to other treatments[10]

Treatment-resistant depression has been discussed widely for years, but treatment resistance in PTSD—another common, serious, disabling condition—has been less frequently addressed in the literature. While 70% of the world’s population has been exposed to a traumatic event, only 5.6% meet DSM-5 criteria for PTSD.1 Moreover, 44% of patients with a PTSD diagnosis recover even without specific treatment.2

Trauma-focused cognitive-behavioral therapy (TF-CBT), such as prolonged exposure therapy, cognitive-processing therapy, or eye movement desensitization and reprocessing, has been recommended as first-choice treatment for chronic PTSD.3-6 TF-CBT and non–trauma-focused CBT may be equally effective post-treatment; TF-CBT has been found to be more effective at 1 to 4 months’ follow-up.7 However, there is a high dropout rate from these treatments. Two-thirds of veterans who complete cognitive-processing therapy or prolonged exposure therapy retain a PTSD diagnosis despite large within-group effect sizes7; significant sleep problems often persist, and there are less data about longer-term follow-up.8

CASE VIGNETTE

Ms. A, 55 years old, has had depression, panic attacks, insomnia, and social withdrawal that have not benefited from trials of citalopram, paroxetine, and sertraline over the past 3 years. At intake, she describes persistent grief for the past 10 years since witnessing the shooting death of her son. She is unable to describe the incident, exhibits the conviction that she is responsible for the death, and has difficulty acknowledging that her child is gone. She persistently re-experiences the traumatic event with a mixture of sadness, anger, and guilt. Her anxiety consists of extreme social avoidance and hypervigilance, and she has frequent nightmares.

Mr. B is a 66-year-old Vietnam combat veteran. Over the nearly 40 years since the Vietnam War, he has been able to work in an administrative position and raise a family, without substance use disorder, serious general medical conditions, or legal problems. On the other hand, besides his work and involvement in a Veterans Service Organization, he has engaged in little social activity with his family or otherwise—no concerts, ballgames, movies, holiday parties, etc. He has undergone multiple unsuccessful pharmacology trials. At presentation, he is taking 200 mg of sertraline and 2500 mg of divalproex daily, and 4 mg of clonazepam and 500 mg of quetiapine daily at bedtime. He has persistent insomnia, severe combat nightmares, angry hyperarousal, and hypervigilance.

Treatment nonresponse

Only 2 medications have FDA indications for PTSD: paroxetine and sertraline. Some treatment guidelines recommend these or other antidepressants, including fluoxetine and venlafaxine, as equivalently first choice with focused CBT.9 Others regard focused CBT as having better evidence and suggest antidepressants only when therapy has failed or is not available, or in cases of severe depression.5,9 This reflects a number of negative randomized clinical trials (RCTs) with SSRIs, and small-to-moderate effect sizes relative to TF-CBT.

Many patients remain symptomatic and functionally impaired despite standard treatments and require alternative interventions. In a review of the pertinent literature on treatment-resistant PTSD, it was found that only 53% of 167 RCTs, open-label studies, and case series that assessed the efficacy of medication other than sertraline or paroxetine described failure of prior pharmacotherapies, and only 3% described failure of TF-CBT. The only RCT of an SSRI (paroxetine) in CBT non-responders failed to show benefit. Systematic investigation of CBT in pharmacotherapy non-responders has also received little investigation. The complexity of the literature did not permit specific recommendations about relative benefits of alternative next-step pharmacologic strategies in paroxetine/sertraline non-responders.10